From Centocor, Malvern, Pa.
Correspondence to Marian T. Nakada, PhD, Centocor, 200 Great Valley Pkwy, Malvern, PA 19355. E-mail nakadam{at}centocor.com
Methods and Results—This study presents a detailed
characterization of the
Conclusions—As an antagonist of not only GP IIb/IIIa
but also
Murine 7E3 IgG (at single high concentrations) has been previously
shown to inhibit (1)
Cell Type and Species Cross-Reactivity
Cell Adhesion
Redistribution Studies
Abciximab binding to HUVECs was competitively inhibited by LM609 IgG,
an
[125I]abciximab bound with similar affinity to
a variety of human primary cell lines, including HUVECs,
coronary artery endothelial cells,
coronary artery smooth muscle cells, and skeletal muscle cells
(Table 2
To determine the potency of abciximab inhibition of
Platelet-bound abciximab has been shown to move from platelet
to platelet.27 28 A similar redistribution
occurred between
M21 cells that express
Redistribution of FITC-abciximab between GP IIb/IIIa and
Abciximab bound to cell-expressed and purified
Abciximab effectively blocked
Previous studies have documented the ability of abciximab to
redistribute in vitro27 and in
vivo28 between platelets. This is attributed
to the ability of the antibody to bind rapidly but reversibly to GP
IIb/IIIa. This characteristic provides the drug with a long
platelet-bound half-life, with antibody detected on platelets
as long as 2 weeks after therapy.28 This
occupancy is associated with a prolonged inhibition of platelet
function in response to shear stress for up to 1
week.29 Because abciximab binds to both GP
IIb/IIIa and
Although
This study provides in vitro evidence for the ability of abciximab to
bind with high affinity to
Received January 27, 1998;
revision received April 16, 1998;
accepted May 1, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Abciximab (ReoPro, Chimeric 7E3 Fab) Demonstrates Equivalent Affinity and Functional Blockade of Glycoprotein IIb/IIIa and
vß3 Integrins
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Large, randomized, and
blinded clinical trials (EPIC, EPILOG, and CAPTURE) have demonstrated
that abciximab (ReoPro, chimeric 7E3 Fab) markedly reduces thrombotic
events associated with percutaneous transluminal
coronary interventions. The marked early benefits at 30 days
were sustained at 6 months and 3 years. Initially developed because of
its efficacy in blocking GP IIb/IIIa
(IIb/ß3) receptors on platelets,
abciximab also binds with equivalent affinity to
vß3. vß3 interaction,
including the ability of abciximab to (1) bind with comparable affinity
to vß3 and GP IIb/IIIa, (2) inhibit
vß3 and GP IIb/IIIa–mediated cell
adhesion in vitro with IC50 values approximating binding
KD values, and (3) redistribute between GP
IIb/IIIa and vß3 integrins in
vitro. vß3, abciximab may provide
additional clinical benefit in preventing
vß3-mediated effects such as thrombin
generation, clot retraction, or smooth muscle cell migration and
proliferation. Abciximab binds with equivalent affinity to both GP
IIb/IIIa and vß3 and redistributes between
the 2 integrin receptors in vitro. Abciximab has been previously shown
to circulate on platelets for up to 2 weeks. Taken together, these
findings suggest that abciximab may have the ability to inhibit both GP
IIb/IIIa and vß3 for extended periods.
Key Words: glycoproteins • antibodies • platelet aggregation inhibitors
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abciximab, an
approved agent for use in patients undergoing
percutaneous coronary intervention, is an
effective antithrombotic agent because of its ability to bind to
glycoprotein (GP) IIb/IIIa
(IIb/ß3) and potently
inhibit platelet aggregation. EPIC,1
EPILOG,2 and CAPTURE,3 3
large, randomized, double-blinded, placebo-controlled trials,
demonstrated that abciximab is safe and effective in reducing the
number of thrombotic ischemic events after
percutaneous coronary intervention. The
parental form of abciximab, murine 7E3 IgG (m7E3 IgG), was also shown
(at a single high concentration) to bind to a related integrin,
vß3,4
also known as the vitronectin receptor. The
vß3 receptor is
expressed on platelets,5
osteoclasts,6 tumor cells,7
and endothelial8 and smooth
muscle cells9 and is upregulated during
angiogenesis10 and wound
healing.11 Functions of this receptor include
cell adhesion,4
proliferation,7 and
migration12 ; bone
resorption6 ; and platelet-mediated thrombin
generation.13 vß3-mediated cell and
platelet adhesion,4 5 (2)
vß3-mediated sickle
red blood cell adherence to human umbilical vein
endothelial cells
(HUVECs),14 (3)
vitronectin-coated bead binding to
endothelial cells,15 (4) adhesion
of GP IIb/IIIa–expressing cells to
HUVECs,16 and more recently (5) angiogenesis
in an in vivo SCID mouse-human skin model.17 The
purpose of this study was to provide a more complete characterization
of the affinity, cell type, and species specificity of binding of
abciximab to vß3 and
to determine more quantitatively the effect of abciximab on
vß3-mediated
effects.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Binding to Purified vß3
vß3 was
purified from M21 melanoma cells kindly provided by Dr Joseph
Jakubowski (Eli Lilly, Indianapolis, Ind) and coated at 0.5 µg/mL
onto 96-well Linbro plates (Flow/ICN) for 2 hours at room
temperature and blocked. Abciximab was iodinated
with Iodobeads (Pierce Chemicals), diluted in HEPES-buffered saline
with calcium (HBSS, JRH Bioscience) containing 1 mmol/L
MgCl2, added to
vß3-coated wells, and
incubated for 4 hours at 37°C. Wells were washed, and bound
radioactivity was counted in a gamma counter. Data were
analyzed by nonlinear regression with GraphPad Prism.
Statistics were performed with the 2-tailed Student's
t test.
Primary human cell lines and growth media were purchased from
Clonetics Corp. Cells were grown to confluence, and
[125I]abciximab in M199 media (JRH Bioscience)
containing 10% FCS and 0.02% azide was added to the cells and
incubated for 2 hours at 37°C. Cells were washed, and bound
radioactivity was quantified and analyzed as described. Primary
cell lines from nonhuman sources were purchased from Cell Systems, rat
aortic smooth muscle cells were a gift from Dr G. Stouffer (University
of Texas, Medical Branch, Galveston, Tex), and established cell lines
were from ATCC. Murine 7E3 IgG was added to confluent cells and
incubated for 2 hours at 37°C.
[125I]anti-mouse secondary antibody [goat
anti-mouse IgG F(ab')2, 1 µCi/µg, Jackson
ImmunoResearch] was used to detect m7E3 IgG.
Vitronectin (Collaborative Biomedical Products)
at 5 µg/mL was coated on 96-well ELISA plates for 2 hours at room
temperature and blocked. M21 cells were labeled with
111In (DuPont/NEN) for 15 minutes in the presence
of 400 nmol/L tropolone (Sigma Chemical Co). Washed cells were
resuspended in HBSS and incubated with antibody for 4 hours at 37°C.
Anti-vß5 (GIBCO)
monoclonal antibody ascites clone P1F6 was used at 1:3000 dilution when
indicated. Cells were added to vitronectin-coated plates
and incubated for 1 hour at 37°C. Plates were washed twice, and bound
radioactivity was quantified with a gamma counter. For human
erythroleukemia (HEL) cell adhesion, cells were labeled with
0.15 µg/mL calcein (Molecular Probes) for 15 minutes at 37°C and
washed. Assay plates were read on a Labsystems Fluoroskan II plate
reader and analyzed as described.
HEL cells (expressing GP IIb/IIIa) or M21 cells (expressing
vß3) were labeled with
FITC-abciximab (20 µg/mL for 30 minutes) and washed. An equal number
of FITC-abciximab–labeled and unlabeled cells were added and incubated
at 37°C on a rotator at 300 rpm. At various times, cells were removed
and fixed with 1% formaldehyde for 5 minutes at room
temperature. Fixed samples were diluted and analyzed on
a Becton Dickinson FACScan flow cytometer. Dual-label experiments were
performed to demonstrate the heterologous redistribution of abciximab
from GP IIb/IIIa to
vß3 and vice versa.
HEL cells either were labeled with FITC-abciximab and washed or were
sequentially labeled with 10E5 IgG (anti–GP IIb/IIIa, Centocor),
treated with R-phycoerythrin (RPE)–goat anti-mouse
F(ab')2 (Accurate Chemical and Scientific Corp),
and fixed with 1% formaldehyde. M21 cells either were labeled with
FITC-abciximab or were sequentially labeled with A10 IgG
(anti-vß3, Centocor)
and RPE–goat anti-mouse F(ab')2 and then fixed.
Fixation of the cells prevented the detection antibody from
dissociating from cells during the experiment. Heterologous cells
labeled with FITC or RPE were mixed and incubated, and at various
times, cells were removed, fixed with 1% formaldehyde, diluted, and
analyzed by flow cytometry. Redistribution was assessed by the
ability of FITC-abciximab to equilibrate from the RPE-negative cells to
the RPE-positive cells.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Saturation binding experiments (Table 1
) revealed that the affinity of
abciximab for HUVECs (KD=9.8±2.7 nmol/L)
was similar to that for purified
vß3,
(KD=11.0±3.2 nmol/L) and to GP IIb/IIIa on
platelets (KD=6.2±2.7 nmol/L). Binding
experiments revealed an 
2-fold difference in the total number of
antibodies binding at saturation for HUVECs
(Bmax=490 000±160 000 sites per cell for
abciximab, 210 000±89 000 sites per cell for m7E3 IgG),
consistent with the monovalent binding of abciximab and
bivalent binding of m7E3 IgG observed previously for
platelets.18 The binding to monolayer
cultures represented receptors accessible to the antibody,
although preliminary experiments that showed comparable maximal binding
of abciximab to monolayer versus suspension cultures suggested that the
Fab fragment bound to both luminal and abluminal receptors. The actual
number of abciximab binding sites on HUVECs reported here does not
necessarily reflect the level of expression in vivo because the
cultured cells used were continually proliferating. Because cells were
grown in FCS, it was possible that endogenous ligands
occupied vß3 receptors
and affected the affinity or receptor number bound by abciximab. Acid
treatment of HUVECs to remove potentially bound ligand from
vß3 receptors did not
affect the affinity or Bmax of abciximab
binding (data not shown). The
vß3 receptor can exist
in different activation states.19 20 21 The ability
of abciximab to recognize both the inactive and active conformation of
vß3 was suggested by
the fact that PMA, which has been shown to activate
vß3,20 did not affect the
affinity or receptor number of abciximab binding (data not shown).
Unfortunately, the absence of an activation-dependent positive control
antibody in this experiment precludes a definitive conclusion.
View this table:
[in a new window]
Table 1. Abciximab Binding to and Blocking of GP IIb/IIIa and
vß3vß3
complex–dependent antibody (Figure 1).
Negative control antibody 10E5 IgG, which binds to GP IIb/IIIa but does
not recognize vß3, and
MT412 Fab, a chimeric Fab fragment that binds to CD4, did not compete
for abciximab binding (Figure 1), thereby demonstrating the specificity
of abciximab binding to
vß3.
View larger version (20K):
[in a new window]
Figure 1. Competition binding of antibodies with
[125I]abciximab for binding to HUVECs. HUVECs were
incubated with 1 µg/mL [125I]abciximab in the presence
of increasing concentrations of unlabeled competitor. LM609 binds to
vß3, 10E5 binds to GP IIb/IIIa, and MT412
binds to CD4. Data points represent mean±SEM of triplicate
determinations.). No binding was seen on
keratinocytes or bronchial epithelial cells, which have
been reported not to express
vß3.22
The species cross-reactivity profile of abciximab was determined by use
of primary and established cell lines. Murine 7E3 IgG bound to cells
from human, baboon, and rhesus monkey with relative high affinity
(Table 3). Murine 7E3 IgG also bound to
canine and rat cells but with only moderate affinity; it bound with
even lower affinity to guinea pig cells. Murine 7E3 IgG did not bind to
bovine, feline, or rabbit cells at concentrations as high as 20
µg/mL. These cells were determined to be positive for
vß3 expression by
their reactivity with LM609 IgG.
View this table:
[in a new window]
Table 2. Cell Type Reactivity of 125I-Abciximab
View this table:
[in a new window]
Table 3. Species Cross-Reactivity Profile of Murine 7E3 IgG1 vß3 and GP IIb/IIIa,
cell adhesion experiments were performed with M21 melanoma cells that
express vß3 but not GP
IIb/IIIa23 and with HEL cells that express GP
IIb/IIIa but not
vß3.24
Cells were preincubated for 4 hours at 37°C with antibodies to ensure
equilibrium binding of the antibodies. Subsequent experiments
demonstrated that equilibrium was reached at 1 hour for abciximab and
at 2 hours for m7E3 IgG, consistent with previous
studies with 7E3 Fab and IgG binding to platelet GP
IIb/IIIa.25 Abciximab and m7E3 IgG both inhibited
M21 cell adhesion to vitronectin-coated plates (Figure 2A). LM609 IgG also blocked binding to a
similar extent, whereas 10E5 IgG had no effect. Maximal inhibition seen
with abciximab, m7E3 IgG, or LM609 IgG was not complete and reached
only 65%. Previous reports described an
vß5-mediated component
of adhesion of M21 cells to
vitronectin,26 so a polyclonal
anti-vß5 antibody was
coincubated with the cells. This resulted in complete inhibition of M21
cell adhesion to vitronectin-coated plates by abciximab,
m7E3 IgG, and LM609 IgG (Figure 2B). IC50 values
were similar to those obtained in the absence of
anti-vß5. Indirect
binding experiments using a secondary detection antibody suggested that
M21 cells expressed one half the number of
vß5 receptors than
vß3 receptors and an
equivalent number of ß1 and
vß3 integrins (data
not shown). ß1 receptors did not appear to play
a role in cell adhesion in this system because
vß3 and
vß5 antibodies
together completely blocked cell adhesion. HEL cell adhesion to
vitronectin-coated plates was similarly inhibited by
abciximab, m7E3 IgG, and the GP IIb/IIIa–specific blocking antibody
10E5 (Figure 3). The
IC50 values for blocking of
vß3 and GP
IIb/IIIa–mediated cell adhesion by abciximab are shown in Table 1
.
View larger version (33K):
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Figure 2. Effect of abciximab on
vß3-mediated M21 melanoma cell adhesion.
M21 cells, expressing vß3, were
111In-labeled, preincubated with antibody in the absence
(A) or presence (B) of anti-vß5, and added
to vitronectin-coated plates. Unbound cells were removed
and bound cells quantified with a gamma counter. Data are expressed as
mean±SEM of duplicate determinations. IC50 values were
calculated by nonlinear regression of data.
View larger version (15K):
[in a new window]
Figure 3. Effect of abciximab on GP IIb/IIIa–mediated HEL
cell adhesion. HEL cells, expressing GP IIb/IIIa, were
fluorescently labeled with calcein, preincubated with
antibody, and added to vitronectin-coated plates. Unbound
cells were removed and bound cells quantified with a Labsystems
Fluoroskan II fluorescence plate reader. Data are expressed as
mean±SEM of triplicate determinations. vß3
and vß3 and between
vß3 and GP IIb/IIIa,
as examined with FACS analysis. FITC-conjugated abciximab was
incubated with HEL cells that express GP IIb/IIIa but not
vß3. Cells were washed
to remove unbound FITC-abciximab, and an equal number of unlabeled HEL
cells were added. Bound FITC-abciximab was measured immediately after
mixing and at the indicated intervals during the incubation. Results of
a representative experiment are shown in Figure 4. At the time of mixing, 2 distinct
populations were seen. With time, the fluorescence of the
positive population (right) decreased (peak shifting to the left) and
that of the negative population (left) increased (peak moving to the
right), eventually resulting in complete merging of the 2 populations
into a single, unimodal peak. The mean fluorescence at
equilibrium (t=2 hours) was 50% of the mean fluorescence of
the original labeled cell population. In 3 separate experiments, a
unimodal peak was apparent within 2 hours. Consistent with
these findings, the t1/2 of
[125I]abciximab dissociation from HEL cell GP
IIb/IIIa was 2 hours (data not shown).
View larger version (24K):
[in a new window]
Figure 4. Abciximab redistribution from GP IIb/IIIa to GP
IIb/IIIa. An equal number of FITC-abciximab–labeled and
unlabeled HEL cells expressing GP IIb/IIIa were combined and samples
were removed at the indicated times, fixed, and evaluated by flow
cytometry. At t=0, 2 separate peaks were observed for
FITC-abciximab–labeled cells (right) and unlabeled cells (left). Both
peaks merged into a uniform peak within 2 hours. vß3 were used, and
redistribution was observed from
vß3 to
vß3 (Figure 5). M21 cells that were bound with
FITC-abciximab formed the peak on the right at t=0 in Figure 5, and the
unlabeled M21 cells were seen as the peak on the left. Within 2 hours,
both peaks merged, indicating that the FITC-abciximab dissociated and
bound to available vß3
sites on the unlabeled M21 cell population. The
t1/2 of [125I]abciximab
dissociation from vß3
on M21 cells was 2 hours (data not shown), similar to that observed
for binding to GP IIb/IIIa.
View larger version (23K):
[in a new window]
Figure 5. Abciximab redistribution from
vß3 to
vß3. An equal number of
FITC-abciximab–labeled and unlabeled M21 cells expressing
vß3 were combined, and samples were
removed at the indicated times, fixed, and evaluated by flow cytometry.
At t=0, 2 separate peaks were observed for FITC-abciximab–labeled
cells (right) and unlabeled cells (left). Both peaks merged into a
uniform peak within 2 hours.vß3 also occurred. The
number of integrin receptors expressed on HEL cells and M21 cells was
not equivalent. HEL cells expressed 20 000 GP IIb/IIIa receptors
per cell, whereas M21 cells expressed 300 000
vß3 receptors per
cell. With this difference in receptor number, a unimodal peak would
not be observed at equilibrium after redistribution. Therefore, a
double-label technique was used that allowed determination of
FITC-abciximab binding to each separate cell population. For
redistribution from
vß3 to GP IIb/IIIa,
M21 cells were bound with FITC-abciximab and mixed with unlabeled HEL
cells. FITC-abciximab redistributed from the
vß3 on M21 cells to
the GP IIb/IIIa on HEL cells (Figure 6).
In the converse experiment, redistribution from GP IIb/IIIa to
vß3 was also
demonstrated (Figure 7).
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[in a new window]
Figure 6. Abciximab redistribution from
vß3 to GP IIb/IIIa. HEL cells were
incubated with 10E5 IgG, washed, incubated with RPE–goat anti-mouse
F(ab')2, washed, and fixed. HEL cells were mixed with
FITC-abciximab–bound M21 cells, and samples were removed at the
indicated times, fixed, and evaluated by flow cytometry. Redistribution
was assessed by the ability of FITC-abciximab to equilibrate from the
RPE-negative M21 cells to RPE-positive HEL cells.
View larger version (21K):
[in a new window]
Figure 7. Abciximab redistribution from GP IIb/IIIa to
vß3. M21 cells were incubated with A10
IgG, washed, incubated with RPE–goat anti-mouse F(ab')2,
washed, and fixed. M21 cells were mixed with FITC-abciximab–bound HEL
cells, and samples were removed at the indicated times, fixed, and
evaluated by flow cytometry. Redistribution was assessed by the ability
of FITC-abciximab to equilibrate from the RPE-negative HEL cells to
RPE-positive M21 cells.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Although the ability of abciximab to inhibit GP IIb/IIIa–mediated
platelet aggregation is well characterized, the interaction and
potential implications of abciximab binding to the related integrin
vß3 have not been
extensively studied. This report documents the ability of abciximab to
bind with comparable affinity to
vß3 and GP IIb/IIIa,
to prevent vß3 and GP
IIb/IIIa–mediated cell adhesion, and to redistribute between GP
IIb/IIIa and vß3
integrins in vitro. vß3 with an affinity
that was comparable to its binding to GP IIb/IIIa. Abciximab bound to a
variety of human cell lines with an affinity similar to that for
purified vß3. The
species cross-reactivity profile of m7E3 IgG suggests that the use of
abciximab in animal models in species lower than nonhuman primates is
limited. The species cross-reactivity profile was done only with m7E3
IgG, which may not necessarily predict the affinity or efficacy of the
monovalent abciximab in animal models. It is interesting to note that
the cross-reactivity profile of abciximab with platelets (data not
shown) mirrors the data generated here with
vß3-expressing
vascular cells. vß3- and GP
IIb/IIIa–meditated cell adhesion. The IC50
values for inhibition in both assays were similar to the
KD values for binding, suggesting that the
ability of abciximab to block cell adhesion was directly proportional
to the occupancy of
vß3 and GP IIb/IIIa
receptors. vß3 with
similar affinity, it was reasonable to hypothesize that it could
redistribute between the 2 receptors. Abciximab redistributed from GP
IIb/IIIa to GP IIb/IIIa and from
vß3 to
vß3. Dual labeling was
a useful method that allowed the concurrent study of 2 distinct cell
populations. Experiments revealed that abciximab could redistribute
between GP IIb/IIIa and
vß3. The kinetics of
redistribution, which was complete in 2 hours, was correlated with
binding studies, which determined a dissociation half-life of 2
hours for [125I]abciximab binding to GP
IIb/IIIa or vß3. vß3 has been reported
to mediate cell attachment and spreading4 ; cell
survival, migration, and proliferation7 9 10 ;
intimal hyperplasia30 ; and
angiogenesis.10 Platelets adhere to
vitronectin through both GP IIb/IIIa and
vß35 ,
and agonist-stimulated platelets bind osteopontin through
vß321 ,
which may facilitate platelet adhesion to osteopontin-containing
atherosclerotic lesions.31
vß3 can also support
clot retraction32 and a component of
platelet-mediated thrombin generation.13
Thrombin formation by platelets was more effectively inhibited by
7E3 than by antibodies that block GP IIb/IIIa
alone,13 suggesting that
vß3 was also capable
of mediating thrombin generation. A recent report describes the ability
of prothrombin to bind directly not only GP
IIb/IIIa33 but also
vß3.20
This interaction facilitates thrombin formation, providing a possible
mechanism for the observed inhibition of thrombin generation by 7E3.
These data suggest an additional mechanism for abciximab efficacy,
blockade of thrombin generation mediated by
vß3 expressed on
vascular endothelium or smooth muscle cells exposed by
vessel injury. vß3 receptors
appear to mediate many biological processes, it is not clear if any of
these can also be driven by receptors with overlapping functions or if
they are actually blocked by abciximab in patients. The roles and
levels of expression of
vß3 by circulating
cells, including platelets and leukocytes, and by vascular cells,
including endothelial and smooth muscle cells, in
normal and disease states in humans are not completely clear. In
addition, the accessibility and extent of blockade of
vß3 receptors by
abciximab, especially within the vessel wall, are not known. In humans,
at reduced bolus doses (0.15 mg/kg), 88±21% of the injected antibody
was found to be platelet bound 2 hours after
injection.34 Free abciximab was rapidly cleared
from the circulation, and 1 hour after injection, <10% of the dose
was detectable as free antibody.34 It has
therefore been postulated that it is unlikely that a large pool of
vß3 exists that
competes for abciximab binding. This suggests that although
vß3 receptors may be
expressed and bound by abciximab, the total number of accessible
vß3 receptors in the
normal vasculature is much smaller than GP IIb/IIIa receptor
number. vß3 and to prevent
vß3-mediated effects.
In addition, we have shown that abciximab redistributes between both GP
IIb/IIIa and vß3
integrins in vitro. The redistribution of abciximab not only may
provide prolonged efficacy for platelet-mediated effects but also
may allow long-lived efficacy for
vß3-mediated effects.
The physiological and clinical implications of
vß3 binding extend
beyond the ability of abciximab to block platelet and vascular cell
adhesion but suggest that abciximab may potentially continue to inhibit
other vß3-mediated
functions involving cell migration, proliferation, and
platelet-mediated thrombin generation long after cessation of
therapy.
Acknowledgments
We gratefully acknowledge Drs Barry Coller and Harlan Weisman
for helpful discussions, Dr John Ghrayeb for the purification of
vß3, Ellen Lance for
technical advice, and Joanie Wendel for manuscript
preparation.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
vß3 rescues melanoma
cells from apoptosis in three-dimensional dermal collagen.
Proc Natl Acad Sci U S A. 1994;91:8856–8860.
vß3 Integrin
expression in normal and atherosclerotic artery. Circ Res. 1995;77:1129–1135.
vß3
for angiogenesis. Science. 1994;264:569–571.
vß3 on vascular cells
during wound repair. Am J Pathol. 1996;148:1407–1421.[Abstract]
vß3) mediates
platelet adhesion to the luminal aspect of
endothelial cells. Circulation. 1997;96:1809–1818.
vß3 involves
a discrete cation-binding site that regulates conformation.
J Biol Chem. 1996;271:1364–1370.
vß3 on vascular cells.
Blood. 1997;90:286. Abstract.
vß3 on platelets
and lymphocytes binds to the matrix protein osteopontin. J
Biol Chem. 1997;272:8137–8140.
vß3 and
vß5 contribute to cell
attachment to vitronectin but differentially distribute on
the cell surface. J Cell Biol. 1991;113:919–929.
vß3 integrin blockade
potently limits neointimal hyperplasia and lumen
stenosis following deep coronary arterial
stent injury: evidence for the functional importance of integrin
vß3 and osteopontin
expression during neointima formation. Cardiol
Res. 1997;36:408–428.
IIbß3.
Blood. 1995;86:2606–2615.
vß3 and GP IIb/IIIa in vitro. Abciximab
also redistributes in vitro between GP IIb/IIIa and
vß3 integrins. As an
antagonist of both GP IIb/IIIa and
vß3, abciximab may offer added clinical
benefit by preventing vß3-mediated effects
such as thrombin generation, clot retraction, or smooth muscle cell
migration and proliferation. Abciximab has been previously shown to
circulate on platelets for up to 2 weeks. These findings suggest
that abciximab may continue to inhibit both GP IIb/IIIa and
vß3 after therapy has ceased.
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